Phencyclidine (PCP) was developed as a surgical anesthetic in the early 1960's but now it has emerged as the latest problem in drug abuse. Since the late 1960's, its recreational use has steadily increased and today it represents a major health problem. PCP at lower doses produces psychological effects that users find reinforcing. At higher doses, PCP can be very toxic, causing stupor or coma which can last up to several days. Often, a prolonged recovery period can follow which is marked by a schizophreniform state. There are suggestions that metabolism and distribution of PCP are involved in its behavioral and toxic effects but appropriate investigations are lacking. The objective of this proposal is to correlate the pharmacokinetics of PCP with its behavioral effects in the same animal after both acute and chronic treatment. Several different species will be compared which will assist in determining what relevance our results have to man. In addition, animals will be exposed to PCP using the routes of administration that the drug abuser employs (smoking and oral). We will use gas chromatography/mass spectrometry to identify, as well as quantitate, PCP, its pyrolytic products, and their metabolites in rats and monkeys that have been treated acutely and chronically with PCP. We have already shown that both route of administration and body weight effect the behavioral activity of PCP. We are particularly interested in smoke inhalation since it is a common method of abuse. Prior to exposing animals to PCP smoke, pyrolytic products will be identified and the concentration of PCP and the degradation products will be measured in smoke. We will attempt to establish the functional significance of metabolism and distribution by PCP in mice, rats, and monkeys. We will correlate the behavioral effects of PCP and mice to the time course of PCP and/or metabolites. We will determine the contribution of pharmacokinetic factors to the development of tolerance to the behavioral effects in rats and monkeys.